title: Sulforaphane inhibits PDGF-induced proliferation of rat aortic vascular smooth muscle cell by up-regulation of p53 leading to G1/S cell cycle arrest.
abstract: Vascular diseases such as atherosclerosis and restenosis artery angioplasty are associated with vascular smooth muscle cell (VSMC) proliferation and intimal thickening arterial walls. In the present study, we investigated the inhibitory effects of sulforaphane, an isothiocyanate produced in cruciferous vegetables, on VSMC proliferation and neointimal formation in a rat carotid artery injury model. Sulforaphane at the concentrations of 0.5, 1.0, and 2.0 μM significantly inhibited platelet-derived growth factor (PDGF)-BB-induced VSMC proliferation in a concentration-dependent manner, determined by cell count. The IC50 value of sulforaphane-inhibited VSMC proliferation was 0.8 μM. Sulforaphane increased the cyclin-dependent kinase inhibitor p21 and p53 levels, while it decreased CDK2 and cyclin E expression. The effects of sulforaphane on vascular thickening were determined 14 days after the injury to the rat carotid artery. The angiographic mean luminary diameters of the group treated with 2 and 4 μM sulforaphane were 0.25±0.1 and 0.09±0.1 mm², respectively, while the value of the control groups was 0.40±0.1 mm², indicating that sulforaphane may inhibit neointimal formation. The expression of PCNA, maker for cell cycle arrest, was decreased, while that of p53 and p21 was increased, which showed the same pattern as one in in-vitro study. These results suggest that sulforaphane-inhibited VSMC proliferation may occur through the G1/S cell cycle arrest by up-regulation of p53 signaling pathway, and then lead to the decreased neointimal hyperplasia thickening. Thus, sulforaphane may be a promising candidate for the therapy of atherosclerosis and post-angiography restenosis.
authors.affiliation: College of Pharmacy, Research Center for Bioresource and Health, Chungbuk National University, Cheongju, Republic of Korea.
authors.forename: Su-Hyang
authors.initials: SH
authors.lastname: Yoo
authors.forename: Yong
authors.initials: Y
authors.lastname: Lim
authors.forename: Seung-Jung
authors.initials: SJ
authors.lastname: Kim
authors.forename: Kyu-Dong
authors.initials: KD
authors.lastname: Yoo
authors.forename: Hwan-Soo
authors.initials: HS
authors.lastname: Yoo
authors.forename: Jin-Tae
authors.initials: JT
authors.lastname: Hong
authors.forename: Mi-Yea
authors.initials: MY
authors.lastname: Lee
authors.forename: Yeo-Pyo
authors.initials: YP
authors.lastname: Yun
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D000077214:Becaplermin; D002339:Carotid Arteries / Q000187:drug effects / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D019927:Cyclin E / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects; D017879:Isothiocyanates / Q000494:pharmacology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D058426:Neointima / Q000188:drug therapy / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016196:S Phase / Q000187:drug effects; D013454:Sulfoxides; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D054462:p21-Activated Kinases / Q000378:metabolism
chemical_list: D019927:Cyclin E; D017879:Isothiocyanates; D018809:Proliferating Cell Nuclear Antigen; D020574:Proto-Oncogene Proteins c-sis; D013454:Sulfoxides; D016159:Tumor Suppressor Protein p53; D000077214:Becaplermin; C515906:Pak1 protein, rat; D054462:p21-Activated Kinases; C495892:Cdk2 protein, rat; D051357:Cyclin-Dependent Kinase 2; C016766:sulforaphane
keywords: Angioplasty; PDGF-BB; Sulforaphane; Vascular smooth muscle cell; p53